Recent advances in the treatment of peritoneal dissemination of gastrointestinal cancers by nucleoside antimetabolites

Abstract

Peritoneal dissemination is the most common cause of metastasis from malignancies in the abdominal cavity. There are no standard treatments for peritoneal dissemination and the results are poor. The reasons for this are as follows: (1) no effective chemotherapeutic agents have been identified or developed; (2) surgical cytoreduction has little effect on survival improvement; and (3) the molecular mechanisms of peritoneal dissemination have not been clarified and no therapy against the target molecules has been developed. However, studies on the molecular mechanisms of peritoneal dissemination have elucidated some of the target molecules and the development of new multimodal therapies has also improved survival. Early postoperative intraperitoneal chemotherapy, hyperthermic intraperitoneal perfusion chemotherapy and neoadjuvant intraperitoneal-systemic chemotherapy have been newly developed, and a novel surgical therapy named peritonectomy has been proposed to perform complete cytoreduction of peritoneal dissemination. At present, these approaches appear to be effective therapeutic modalities for peritoneal dissemination. However, TS-1 and capecitabine have shown worthwhile results in recent clinical trials for patients with advanced gastric cancer. We recently found that newly developed antitumor cytosine nucleoside analogs show a survival advantage in peritoneal dissemination models using human cancer cells. These non-fluoropyrimidine nucleosides may potentially help to improve the poor prognosis observed in patients with advanced cancers involving peritoneal dissemination. (Cancer Sci 2007; 98: 11-18) P eritoneal dissemination remains the most difficult type of metastasis to treat, and almost all surgeons believe that an operation is not indicated for such metastasis.(1-3) Systemic chemotherapy tends to have little effect on the treatment of peritoneal dissemination, because the peritoneal-blood barrier existing between mesothelial cells and the submesothelial capillary hinders drug distribution throughout the peritoneal cavity. Recent advances in the studies of new drugs and multimodal therapies have proposed the therapeutic potency for advanced cancer with peritoneal dissemination. Neoadjuvant chemotherapy is also known to reduce the tumor burden, thus resulting in a stage reduction. As a result, the incidence of complete cytoreduction may increase after neoadjuvant chemotherapy. A new type of neoadjuvant intraperitoneal-systemic chemotherapy (NIPS) has been developed to increase the rate of complete cytoreduction. The complete removal of peritoneal dissemination is an independent prognostic factor. A peritonectomy is a novel surgical procedure by which complete cytoreduction for peritoneal dissemination is performed.(5-8) These approaches are now being carried out as treatment modalities for peritoneal dissemination from appendiceal, colon and gastric cancer. Furthermore, several recent phase II studies that evaluated the efficacy of new anticancer drugs including taxanes, TS-1 and capecitabine have shown p...

Clinical significance of telomerase activity in peritoneal lavage fluid from patients with gastric cancer and its relationship with cellular proliferation

“…The positive rate of tolemerase activity of the 37 specimens with serosal invasion was 54.1% (20/37), while PLC positive rate of those was 32.4% (12/37). As we know, serosal invasion appears to be mainly responsible for the exfoliation of free cancer cells into the peritoneal cavity [11] . It has been reported that approximately half of patients with serosal invasion develop peritoneal recurrence even if curative resection is performed [6,7,28] .…”

“…Free cancer cells exfoliated from cancer lesions have been postulated as the main cause of metastasis [5,[8][9][10] . Recent advances on the molecular mechanisms of peritoneal dissemination have elucidated some of the target molecules and the development of new multimodal therapies in an attempt to eliminate peritoneal exfoliated www.wjgnet.com free cancer cells has also improved survival [11] . Of course, it is very important to develop reliable methods for the accurate selection of patients for whom adjuvant intraperitoneal therapy will be required.…”

Bone marrow and peripheral blood expression of ID1 in human gastric carcinoma patients is a bona fide indicator of lymph node and peritoneal metastasis

“…There is no conclusive evidence, however, whether peritoneal dissemination might be established by the lymph node metastasis as well as direct dissemination from the serosal layer of stomach (Yonemura et al, 2007). In this study, the ID1 mRNA expression in bone marrow and peripheral blood was significantly associated with lymph node metastasis and peritoneal dissemination.…”

Screening and identification of peritoneal metastasis-related genes of gastric adenocarcinoma using a cDNA microarray

“…Peritoneal dissemination is the most frequent type of recurrence in advanced gastric cancer (Jemal et al, 2005;Yoshikawa et al, 2006;Yonemura et al, 2007), and the prognosis for dissemination is the worst among the recurrence patterns of gastric cancer, with a mean survival of 6 months. Previous research indicated that peritoneal dissemination is required in many steps of the complex metastatic process, including the interaction of many genes along with their products, self-regulation, and interference with multiple signal transduction pathways (Yanagihara et al, 2005;Motoori et al, 2006).…”